Hemodynamic Assessment of Stable, Intermediate Lesions in the Catheterization Laboratory Using FFR or iFR

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Introduction

Since its introduction, coronary angiography has been uniformly accepted as the gold standard for assessing the presence and extent of coronary artery disease. Coronary anatomy described by angiography is the main and often only piece of evidence leading to revascularization decisions.

In particular, 50% diameter stenosis has been identified as the threshold value to justify revascularization, to serve as an endpoint in studies on revascularization strategies, and to validate noninvasive techniques.1 Early animal experiments showed that hyperemic myocardial flow reserve started to decline below 4.0 when diameter stenosis was ≥50% or below 3.0 when diameter stenosis was ≥70%.2 In humans with proven atherosclerosis, this relationship between diameter stenosis and myocardial blood flow is substantially diminished by a very large scatter3 or even absent,4 with scarce relation to ischemia, left ventricular function, or clinical outcomes.

Recent studies have further shown that the relationship between diameter stenosis and functional relevance, as investigated by fractional flow reserve (FFR), is modest at best, with significant discordance in at least one third of the cases that may lead to inappropriate decisions regarding revascularization strategy.5,6 The latter emphasizes the need for proper functional evaluation as justification of performing or deferring revascularization, regardless of angiographic severity.1

FFR

FFR is the most studied index to determine the hemodynamic significance of a given epicardial coronary stenosis. It can be defined as the ratio of maximal achievable blood flow in a myocardial bed in the presence of an epicardial stenosis to the theoretical normal maximal flow in the same myocardial distribution.7 Thus, FFR represents what percentage of normal maximal flow is still achievable despite the resistance offered by a coronary stenosis. For instance, an FFR of 0.7 means that in a given coronary artery with a stenosis, it is possible to reach only 70% of the maximal blood flow had the artery been free of atherosclerotic lesions. Similarly, FFR value estimates to what extent revascularization can increase hyperemic myocardial flow if physiologic conditions are fully restored and a post- percutaneous coronary intervention (PCI) FFR value of 1.0 is reached. In other words, with an FFR of 0.7, a relative 43% or absolute 30% increase in blood flow can be expected after revascularization.

According to Darcy's law, flow equals driving pressure divided by resistance. Under maximal hyperemia, resistance is constant and minimal, and so a linear relationship between flow and pressure is established. FFR exploits this physiological phenomenon and the irrelevance of coronary venous pressure to allow calculating a ratio of two flows by simply calculating the ratio between the pressure distal to the coronary stenosis and the aortic pressure (Pd/Pa) (Figure 1).8

Figure 1

FFR is calculated simply by the ratio between the pressure distal to the coronary stenosis (Pd) and the aortic pressure (Pa) during maximal hyperemia. This typical pressure tracing illustrates an initial phase of resting pressures, then hyperemic stimulus by rush intracoronary bolus of adenosine, followed by the development of a steady state maximal hyperemic phase.

FFR has many useful features. First, a unique and validated cut-off value set at 0.8. Coronary stenoses with FFR > 0.8 are not associated with ischemia at noninvasive stress tests, and FFR values ≤ 0.8 are almost exclusively found in ischemic myocardial territories.7 Second, the hyperemic response of the microcirculation is very reliable once maximal hyperemia is induced, making FFR measurement highly reproducible. Third, FFR is completely independent of all the changes in hemodynamic condition that can occur during the measurement, such as changes in blood pressure, heart rate, and contractility.9 Fourth, FFR has an unsurpassed spatial resolution, being able to detect the functional significance of a stenosis at almost millimeter level.

Equipment needed for FFR measurement consists of regular PCI material (i.e., guiding catheter and Y-connector). Anticoagulation should be performed as per any routine intracoronary procedure. FFR is mainly measured by a sensor-tipped 0.014-inch pressure guidewire, where the sensor is located 30 mm back from its tip, at the junction of the radiopaque and non-radiopaque part of the wire. The wire-based system is offered by various manufacturers. Another system for FFR measurement is a dedicated maximally 0.036-inch rapid-exchange sensored microcatheter, used over any regular guidewires.

In practice, FFR measurement starts with calibration of the sensor outside of the patient to zero pressure. Second, once the sensor has left the guiding catheter, the two pressuresnamely the one measured by the pressure-sensored device (later indicated as Pd) and the one measured through the guiding catheter (later indicated as Pa)must be equalized. Then it is possible to advance the sensor optimally to the most distal point of the index coronary artery but at least distally to the investigated coronary lesion. At this point, it is important to induce a steady-state maximal hyperemic state. To do so, it is necessary to get rid of any possible epicardial coronary spasm by administering an intracoronary bolus of nitrates (200 mcg intracoronary bolus). Subsequently, microcirculatory vasodilation is induced by either an intracoronary bolus (100 mcg in the right coronary artery or 200 mcg in the left coronary artery) or an intravenous infusion (140 mcg/kg/min) of adenosine.10 Intracoronary injection should be performed briskly so as not to miss the short-lasting hyperemic effect, reaching its maximum around 10-25 seconds after injection. Intracoronary administration is quicker and allows multiple FFR measurements without significantly prolonging procedure time. On the other hand, intravenous infusion is more time-demanding because the peak hyperemic response usually occurs after 1 minute, although it allows pullback pressure measurements that are particularly useful in case of diffuse disease or multiple lesions in a single coronary artery. The lowest Pd/Pa value registered during the hyperemic state is automatically identified by the system as the value of FFR.

It has been validated versus a true gold standard using a sequential Bayesian approach against three noninvasive tests to detect myocardial ischemia: dobutamine stress echocardiography (contractile index of ischemia), exercise testing (electrical index of ischemia), and thallium scintigraphy (perfusion index of ischemia). The sensitivity of FFR < 0.75 in identifying reversible ischemia was 88%, and specificity was 100% with a stunning accuracy of 93%.7

The clinical use of FFR has also been investigated in many studies, the most iconic among which are undoubtedly the DEFER (Deferral Vs. Performance of Percutaneous Coronary Intervention of Functionally Non-Significant Coronary Stenosis) study, the FAME (Fractional Flow Reserve versus Angiography for Guiding Percutaneous Coronary Intervention) trial, and the FAME 2 (Fractional Flow ReserveGuided PCI versus Medical Therapy in Stable Coronary Disease) trial.11-13

The DEFER study was the first randomized trial to investigate the appropriateness of leaving untreated coronary lesions with a non-significant FFR value. Recently, a 15-year follow-up has been published showing the safety of leaving functionally non-significant stenosis non-revascularized regardless of their angiographic appearance. Despite the similar number of deaths, a higher number of myocardial infarctions was reported when stenting such lesions.11

The FAME trial investigated patients with multivessel disease and demonstrated the superiority of an FFR-guided strategy over an angiography-guided strategy in terms of clinical outcome. In addition, it confirmed the very low rate of events in functionally non-significant lesions when left non-revascularized.12

Subsequently, the FAME 2 trial compared the clinical outcome of patients with at least one functionally significant stenosis treated either with PCI on top of medical therapy or with medical therapy alone. Patients in the PCI group had a clinical benefit driven mainly by urgent revascularization. However, in a landmark analysis, from the eighth day to 2 years after enrollment, a better outcome in terms of death and myocardial infarction was also observed, favoring PCI compared with medical therapy alone.13

Resting and Non-Maximal Hyperemic Indices

During the last few years, there has been an effort in researching functional indices of ischemia that do not necessitate maximal hyperemia and, thus, adenosine administration. The reasons for such struggle are various and include

economic considerations,

potential contraindications to the use of adenosine in some patients,

the uneasiness caused in some operators by transient atrio-ventricular blocks, and

avoidance of chest discomfort associated with the administration of the drug.

The most frequently used non-hyperemic index is undoubtedly instantaneous wave-free ratio (iFR). This index is based on the identification, through wave intensity analysis, of a wave-free diastolic period, during which resistance is considered to be naturally minimized. The value of iFR is automatically calculated by a vendor-specific software as the ratio of the mean pressure distal to the stenosis to the mean aortic pressure during the aforementioned time interval.14 Various studies assessed the accuracy of iFR in predicting FFR and reported values ranging 60-90%, with an average accuracy of 80% and a cut-off value around 0.9. Some studies, such as the ADVISE II (Adenosine Vasodilator Independent Stenosis Evaluation II) trial, advocate the use of iFR in a hybrid approach with FFR. A treatment iFR value ≤0.85, a deferral iFR value ≥0.94, and the use of FFR within the 0.86 and 0.93 iFR values ("adenosine zone") resulted in an overall 94.2% classification agreement with a lone-FFR strategy but obviated the need for vasodilators in 65% of patients.15-18

Resting Pd/Pa ratio deserves an important mention within non-hyperemic indices. This index is particularly interesting because it can be calculated with any pressure-monitoring device. A recently published post-hoc analysis of the CONTRAST (Can Contrast Injection Better Approximate FFR Compared to Pure Resting Physiology?) trial showed equivalent diagnostic performance of Pd/Pa and iFR both in stable and unstable patients, suggesting that it could be applied clinically in a similar fashion.21 Still, clinical outcome data supporting the use of resting Pd/Pa are lacking.

Being a potent but still not maximal hyperemic agent,22 contrast media by itself also allows an adenosine-free alternative to FFR, called contrast FFR. An international multicenter study by Johnson et al. reported an accuracy of 85% in predicting FFR.23 Contrast FFR could therefore be an affordable and easy-to-perform alternative to FFR, which, being adenosine-free, could partially overcome the limits of resting indices while maintaining cost-effectiveness and absence of adenosine-related side-effects.

Summary

Based on fundamental clinical data,24 it is clearly declared in the recent revascularization guidelines that coronary revascularization can provide clinical benefit only when it targets relevant myocardial ischemia. Because coronary angiography suffers marked limitations in terms of detecting coronary stenoses' functional significance, additional assessment is needed if noninvasive proof of ischemia is not available. Thanks to extensive validation work in most clinical settings, FFR is considered the gold standard of invasive macrovascular ischemia assessment. Recent clinical data suggest that non-hyperemic indices might offer reliable alternatives as well.